D-cycloserine is a known antituberculous antibiotic [Welch, H. et al. Antibiot. Med. & Clin. Therapy, 1(2), 72, 19551] and is used for administration of once 250 mg, b.i.d. per orally. D-cycloserine is known to show high bioavailability and long half-life as well as good transport into the brain (Nair, K. G. S. et al. Antibiot. Ann., 56, 136-140, 1955 and Mandell, C. L. and Petri, W. A. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th Ed. New York: McGraw-Hill, pp 1164-1165, 1996). It has also known that D-cycloserine selectively acts on the glycine binding site (strychnine-insensitive glycine binding site) of the NMDA (N-methyl-D-aspartate) receptor, which is one of the glutamate receptors, the glutamate is the one of the excitatory neurotransmitter, in the nervous system (Watson, G. B. et al. Brain Res., 510, 158-160, 1990 and Kemp, J. A. and Leeson, P. D. TiPS, 14, 20-25, 1993).
It has reported that D-cycloserine acts on the glycine binding site as a partial agonist to reveal various actions on the central nervous system [Baxter, M. G. and Lanthorn, T. H. CNS Drug Reviews, 1(1), 74-90, 1995]. Among them, treatment of schizophrenia (JP-A-2-225412) and treatment for improving memory disorder in head injury and Alzheimer's disease (WO 96/15787 and WO 96/15788) are known.
However, an improving action of D-cycloserine on the CNS motor (cerebellar) functional disorder has not been known.
Spinocerebellar degeneration develops major symptom of cerebellar or spinal ataxia and is a general name for the ill-defined neuro-degenerative disease having main lesion on the nucleus or neural tracts in cerebellum or spinal cord. Generally, falling develops slowly but is progressive and some disease type is hereditarily expressed. Cranial CT and MRI indicate frequently cerebellar or brain stem atrophy. Major symptom is cerebellar or posterior spinal ataxia, but depending on the disease types, sometimes develops vegetative symptom or spastic paraplegia as well as showing pyramidal or extrapyramidal symptoms. Consequently, the symptoms show multiplicity.
In Japan, the diagnostic criteria of spinocerebellar degeneration was revised by “ataxia” research group, M.H.W. in 1991, and 9 or 10 diseases were temporary mentioned as an individual disease.
A ratio of nonhereditary spinocerebellar degeneration to hereditary spinocerebellar degeneration in Japan is higher than that in Europe and in the U.S. Hereditary spinocerebellar degeneration is frequent in Europe. Nonhereditary spinocerebellar degeneration includes olivopontocerebellar atrophy, Shy-Drager syndrome, striato-nigral degeneration and late cortical cerebellar atrophy. The incidence of spinocerebellar degeneration in Japan is reported mostly olivopontocerebellar atrophy which accounts for the largest in 35%, late cortical cerebellar atrophy in 13%, Shy-Drager syndrome in 7% and striato-nigral degeneration in 1.5%. The ratio of male to female is almost 1:1, but that of male to female in Shy-Drager syndrome is 5:1 which shows prevalent in male. (New Clinic for SCD-Clinic of Spinocerebellar Degeneration—Ed. Itoyama, Yasuto, Shinko Medical Publishers, 1996).
The cerebellar cortex is constructed by three layers of molecular layer, Purkinje cell layer and granule cell layer, and is prevalent to amino acids [excitatory amino acid: glutamic acid (Glu) and inhibitory amino acid: γ-aminobutyric acid (GABA)] as the neurotransmitters. Biochemical changes of spinocerebellar degeneration is different depending on the disease types. In the typical disease type, for example, olivopontocerebellar atrophy, amino acid receptors such as γ-aminobutyric acid B receptor (GABA B receptor) and quisqualic acid receptor are decreased in the molecular layer; NMDA receptor is also decreased in the granule cell layer; and γ-aminobutyric acid A receptor (GABA A receptor) and benzodiazepine receptor are decreased in the granule cell layer and the molecular layer (Albin, R. L,. and Gilman, S. Brain Res., 522, 37-45, 1990). However, an efficacy of agonist for glycine binding site of NMDA receptor on this disease has not been examined.
It has been known that D-serine exists in the mammalian brain as an endogenous substance (Hashimoto, A. et al. J. Neurochem., 60, 783-786, 1993 and J. Neurochem., 61, 348-351, 1993) and D-serine binding site, which is insensitive to DCK (5,7-dichlorokynurenate) antagonist for glycine binding site of NMDA type glutamate receptor, exists in the rat brain, especially in the cerebellum at high concentration (Matoba, M. et al. J. Neurochem., 69, 399-405, 1997). The DCK- and strychnine-insensitive D-serine binding sites are thought to be a new candidate of the site of action for the endogenous D-serine.
As described hereinabove, cause of spinocerebellar degeneration is unknown, consequently the treatment therefor is performed mainly by symptomatic treatment. The drug for treatment of spinocerebellar degeneration approved at present, in Japan is only TRH (thyrotropin-releasing hormone) preparation, which is applied for ataxia, Protirelin tartrate (Mano, Y. et al., Acta Neurol. Scand., 73, 352-358, 1986 and JP-2556193). Since ataxic symptom was improved by an intraperitoneal administration of TRH in the rolling mouse Nagoya, application for treatment of spinocerebellar degeneration was initiated. The therapeutic effect was, however, not sufficient in the prolongation of effect and efficacy and developing adverse effect. Since large amount of administration of TRH preparation is necessary and the administration has to be performed by an injection, patients have to be imposed severe stress. Therefore, development of oral medicine with sufficient therapeutic effect, and slight adverse effect has been expected in the clinical field.